Silent Cerebral Infarction Research Articles

Trimethylamine N-oxide is associated with impaired cognitive function in patients with atrial fibrillation

Abstract Introduction Since patients with atrial fibrillation (AF) are predisposed to suffer from major adverse cerebrovascular events (MACE), they are more likely to suffer MACE linked sequelae, such as cognitive impairment. We hypothesised that the gut microbiome derivate trimethylamine N-oxide (TMAO) may amplify this pathomechanism given its hypercoagulative, proinflammatory and proatherogenic effects. Methods Patients of the Swiss-AF cohort with determined TMAO plasma levels, cognitive scores (n=2'379) and cerebral magnetic resonance imaging (cMRI) (n=1'722) collected at baseline were included. TMAO levels were measured by liquid chromatography-mass spectrometry (HPLC). Overall cognitive performance was evaluated using the Cognitive Construct (CoCo) score reflecting different cognitive functions measured by four validated neuropsychological assessments, namely the Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT parts A and B), Semantic Fluency Test (SFT) and Digital Symbol Substitution Test (DSST). The scores were compared with the quartiles of patients' TMAO plasma levels (Q1: 0.6–4, Q2: 4–5.8, Q3: 5.8–9.1, Q4: 9.1–164μmol/l) in linear effect models. All models were adjusted for multiple covariates correlating with this association: For TMAO (overall meat consumption >3 times per week, physical activity, glomerular filtration rate, presence of diabetes mellitus), cognitive function (EQ-5D-5L score, geriatric depression scale, education level) and cerebral affects (white matter lesions volume and total brain volume in cMRI). The relevance of high TMAO plasma levels in different stroke groups in cMRI (i.e., clinically overt, silent, or no stroke) were analysed in a subgroup analysis. The subgroups were additionally adjusted for total brain volume to eliminate the effect of simultaneous decrease of cerebral white matter. Results After multivariable adjustment, AF patients in the highest quartile of TMAO levels performed significantly poorer in the global cognitive score (CoCo: estimate −0.11, 95% CI [−0.17, −0.05], p=0.002) compared to patients in the lowest quartile. This was observed also in the MoCA, SFT, DSST, TMT-A and TMT-B. In the subgroup analysis, an association between the highest TMAO quartile (compared with the lowest quartile) and lower CoCo score was found in the group of patients with overt strokes (−0.18, 95% CI [−0.33, −0.04], p=0.012). Weak evidence of the same association was found in the group of patients with silent strokes (−0.13, 95% CI [−0.25, 0.002], p=0.053) and patients with no strokes (−0.08, 95% CI [−0.16, 0.01], p=0.07). After adjustment for decreased brain volume, the association remained for silent strokes (−0.14, 95% CI [−0.28, −0.01], p=0.036) indicating the impact of TMAO in this subgroup. Conclusion TMAO plasma levels were associated with cognitive impairment in patients with AF. Longitudinal data will clarify dynamics and likely causality between TMAO and cognitive impairment. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swiss National Science Foundation

Cerebral hemodynamics during atrial fibrillation: computational fluid dynamics (CFD) analysis of lenticulostriate arteries using 7T high-resolution magnetic resonance imaging

Abstract Background Lenticulostriate arteries (LSAs) are small perforating arteries (0.1–1 mm diameter), perpendicularly departing from middle cerebral artery (MCA) and supplying blood flow to important cerebral subcortical and basal ganglia areas. LSAs are involved in silent strokes and cerebral small vessel disease, potentially leading to cognitive decline and vascular dementia. There is growing evidence that atrial fibrillation (AF), the most common cardiac arrhythmia, increases the risk of dementia even in the absence of clinical strokes. AF also increase the risk of small vessel disease. AF may alter deep cerebral hemodynamics per se, however no data exists regarding a possible impact of AF on MCA-LSA branching sites hemodynamics. Purpose To use computational fluid dynamics (CFD) analysis to study the hemodynamics of LSAs-MCA branching sites. Methods 7T high-resolution magnetic resonance imaging (HR-MRI) brain scans (Figure 1, panel a) were used to derive detailed geometrical models of LSAs-MCA branching sites. CFD analysis was then conducted, simulating AF conditions as well as sinus rhythm (SR), at different ventricular rates (from 50 to 130 bpm). Results Geometrical models were retrieved from HR-MRI scans of 7 patients. By means of the most significant metrics, such as wall shear stress (WSS; Figure 1, panel b), wall shear stress gradient (WSSG), and flow velocity (FV), a comparison between SR and AF was performed. Conclusion CFD analysis of LSAs-MCA branching sites using geometrical models derived from HR-MRI brain scans was feasible and allows to quantify the impact of AF on these critical ramifications of the MCA. Funding Acknowledgement Type of funding sources: None.

Silent cerebral infarcts in patients with atrial fibrillation: Clinical implications of an imaging-adjusted CHA2DS2-VASc score.

BackgroundThe CHA2DS2-VASc score does not include silent infarcts on neuroimaging in stroke risk estimation for patients with atrial fibrillation (AF). The inclusion of silent infarcts into CHA2DS2-VASc scoring and its impact on stroke prophylaxis recommendations in patients with AF has not been previously studied. The present study sought to quantify the prevalence of silent infarcts in patients with AF and describe potential changes in management based on magnetic resonance imaging (MRI) findings.MethodsParticipants from the Mayo Clinic Study of Aging with AF and brain MRI were included. Silent infarcts were identified. “Standard” CHA2DS2-VASc scores were calculated for each subject based on clinical history alone and “imaging-adjusted” CHA2DS2-VASc scores based on evidence of cerebral infarction on MRI. Standard and imaging-adjusted scores were compared.ResultsOne hundred and forty-seven participants (average age 77, 28% female) were identified with AF, MRI, and no clinical history of stroke. Overall, 41 (28%) patients had silent infarcts on MRI, corresponding with a 2-point increase in CHA2DS2-VASc score. Of these participants, only 39% (16/41) with silent infarct were on anticoagulation despite having standard CHA2DS2-VASc scores supportive of anticoagulation. After incorporating silent infarcts, 13% (19/147) would have an indication for periprocedural bridging compared to 0.6% (1/147) at baseline.ConclusionsIncorporation of silent infarcts into the CHA2DS2-VASc score may change the risk-benefit ratio of anticoagulation. It may also increase the number of patients who would benefit from periprocedural bridging. Future research should examine whether an anticoagulation strategy based on imaging-adjusted CHA2DS2-VASc scores could result in a greater reduction of stroke and cognitive decline.

Distribution Pattern Analysis of Cortical Brain Infarcts on Diffusion-Weighted Magnetic Resonance Imaging: A Hypothesis-Generating Approach to the Burden of Silent Embolic Stroke.

Background In patients with covert cerebrovascular disease or proximal source of embolism, embolic silent brain infarction may precede major stroke events. Therefore, characterization of particularly cortical silent brain infarction is essential for identifying affected patients and commencing adequate secondary prevention. This study aimed to investigate differences in the distribution pattern of cortical ischemic stroke lesions to assess potential predilection sites of cortical silent brain infarction. Methods and Results We prospectively included all consecutive patients with stroke presenting from January 1 to December 31, 2018. Diffusion-weighted imaging lesions were used to generate voxel-based lesion maps and assigned to atlas-based cortical regions of interest in middle cerebral artery territories. Each region-of-interest lesion frequency was related to the respective region-of-interest volume to identify frequently affected and underrepresented cerebral cortex areas. Diffusion-weighted imaging data for voxel-based lesion maps were available in 334 out of 633 patients. Primary analysis revealed that small- (<0.24 cc) and medium-sized (0.24-2640 cc) lesions distributed predominantly along regions associated with sensorimotor or language function. Detailed analysis within middle cerebral artery territories showed an approximated frequency of missed cortical stroke lesions of up to 67% in the right and 69% in the left hemisphere. In particular, the frontal, temporal, and occipital cortices were underrepresented. Larger lesion size and areas associated with higher cortical function led to hospital admission. Conclusions Cortical brain infarcts in hospitalized patients are not dispersed equally but are predominantly located in brain structures associated with motor control and sensory and language function. Matching underrepresented cerebral cortex regions to symptoms not yet associated with stroke warrants further exploration.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Cough Test Results during Screening for Silent Aspiration Are Affected by Risk Factors for Silent Cerebral Infarct in Older Adults with Chronic Disease.

The cough reflex does not change with age. However, older adults with chronic diseases often have a reduced cough reflex. The effects of several risk factors on reduced cough sensitivity in older adults remain unclear. This study aims to clarify the risk factors for reduced cough sensitivity in older adults with chronic diseases. This cross-sectional study included participants aged <65 years (young group; n = 21), those aged ≥65 years (older adults with chronic disease group; n = 18), and those with dysphagia (dysphagia group; n = 16). A cough test was performed on all participants using an ultrasonic nebulizer with a mist of 1% w/v citric acid physiologic saline. Cough response was observed in the young (21/21), older adult (9/18), and dysphagia (13/16) groups. The difference between the young and older adult groups was significant (p < 0.01). The older adult and dysphagia groups had decreased cough sensitivity compared to the younger group. Cough sensitivity was affected by risk factors for silent cerebral infarct and age. Our findings show that cough test results might be affected by risk factors for silent cerebral infarction in older adults with chronic diseases.

O-02: RADIOMICS AND ARTIFICIAL INTELLIGENCE FOR IDENTIFICATION AND MONITORING OF SILENT CEREBRAL INFARCTS IN SICKLE CELL DISEASE: FIRST ANALYSIS FROM THE GENOMED4ALL EUROPEAN PROJECT

Purpose: The use of Artificial Intelligence (AI) for personalized medicine has recently guided dramatic improvements in the diagnostic pathway of several diseases. The European Project GENOMED4ALL, aims at using European level data of patients affected by Multiple Myeloma, Myelodysplastic Syndromes and Sickle Cell Disease (SCD) to find correlation between genomics – and other omics data – with phenotypic manifestations and seize the opportunity of improving diagnostics through AI. Silent Cerebral Infarcts (SCIs) are a significant determinant of morbidity since childhood in SCD. One of the aims of the SCD clinical case in GENOMED4ALL is the use of radiomics – quantitative method for the evaluation and interpretation of medical images- and AI firstly to develop an automatic and uniform identification and characterization of SCI through the analysis of cerebral MRI, secondly, to correlate imaging data with other types of omics data in order to predict risk of recurrence. Materials and methods: The MRI protocol included 3D-T1, FLAIR and DWI sequences. Neuroradiological reports were cross checked for consistency. A stepwise segmentation (identification of lesion volume), pre-processing and extraction of MRIs was performed utilizing different open-source software: Lesion Segmentation Tools and UNet for segmentation, Freesurfer for brain extraction. To optimize SCI identification, we have selected the best software for segmentation; freesurfer was substituted with a faster approach. Results: Six European SCD centers participated in this first phase of the Radiomics project with 501 MRIs: 225 were classified as abnormal by the local neuroradiologists due to presence of SCI, 275 were normal; 70% were pediatric MRIs. Different instruments were used in the 6 centers: Philips 1.5 T (n.2), Siemens 1.5 T and 3 T (n.2), GE 3T (n.2). A stepwise procedure allowed the optimization of SCI identification, with distinction between SCI and background non clinically significant noise (i.e periventricular areas) or other white matter hyperintensities (i.e transient glial maturation). As shown in Figure 1, to segment SCI in FLAIR MRI, we have used a pre-trained UNet [Li H, 2018]. Firstly, we have extracted the brain registering the MNI152 on the T1 image. Then we have applied the brain mask and a threshold taking only the largest component. The UNet performs the segmentation of hyperintensities. We have removed the regions surrounded by less than the 90% of White Matter or near the brain ventricles to remove non-SCI region. In the end, we have enlarged the remaining ones. To date, segmentation on 303 exams from different centers showed very few false positive and false negatives highlighting the need to take into account different technical characteristics due to the various equipment used in the different centers. Conclusion: SCD is a systemic disorder with extreme phenotypic variability. Radiomics and AI offer the opportunity to seize the potential of big datasets analysis to optimize diagnostic in SCD. SCI can be detected automatically from different datasets. Four more European Centers will add their MRI in the second phase of the project, to increase variability and allow correlation of in detailed Radiomics data (lesion volume, lesion site, etc) with clinical-hematological characteristics and other omics data.Figure 1. Stepwise Segmentation (identification and selection of lesion volume) workflow for automatic selection of all SCI. From left to right: Axial slices of the input scan, Slice after skull stripping to highlight only the brain parenchyma, Segmentatio The authors do not declare any conflict of interest

Psychosocial measures in relation to smartwatch alerts for atrial fibrillation detection

Psychosocial measures in relation to smartwatch alerts for atrial fibrillation detection

Neurocognitive Changes in Sickle Cell Disease: A Comprehensive Review.

Sickle cell disease (SCD) is a type of hemoglobinopathy characterized by abnormal hemoglobin molecules, which includes numerous acute and chronic complications. Ischemic stroke, silent cerebral infarction, headache, and neurocognitive impairment are the most common neurological complications associated with SCD. Acute anemia because of SCD can cause cognitive impairments because of cerebral hypoxia. Cognitive abnormalities in SCD manifest in various aspects such as working memory, verbal learning, executive functions, and attention. These neurocognitive impairments have been associated with poor functional results, such as transitioning from juvenile to adult care, adherence to medications, and unemployment. In this review, we focus on neurocognitive aspects of SCD patients based on different imaging techniques, psychological batteries, associated neuromarkers, and interventions for managing of cognitive deficiencies..

Silent brain infarcts, peripheral vascular disease and the risk of cardiovascular events in patients with hypertension.

We aimed to study the relationship between cerebral small vessel disease (cSVD) lesions, as markers of subclinical target organ damage (TOD) in the brain, and incident cardiovascular events (CVE). Data from the ISSYS (Investigating Silent Strokes in hYpertensives Study), which is a longitudinal and observational study conducted in patients with hypertension aged 50-70 years, and stroke-free at the inclusion. At the baseline visit, participants underwent a clinical interview, a brain MRI, urine and blood sampling collection and vascular testing studies. Therefore, we obtained markers of TOD from the brain [white matter hyperintensities, silent brain infarcts (SBI), cerebral microbleeds and enlarged perivascular spaces (EPVS)], from kidney (microalbuminuria, glomerular filtration) and regarding large vessels [ankle-to-brachial index (ABI), carotid-femoral pulse wave velocity]. Survival analyses were used to assess the relationship between these predictors and the incidence of cardiovascular events (CVE). We followed-up 964 individuals within a median time of 5 years (4.7-5), representing 4377.1 persons-year. We found 73 patients presenting incident CVE, which corresponds to a rate of 8.2%. We found ABI less than 0.9 [hazard ratio, 2.2; 95% confidence interval (CI) 1.17-4.13, P value = 0.014] and SBI (hazard ratio, 2.9; 95% CI 1.47-5.58, P value = 0.002) independently associated with higher risk of incident CVE. The inclusion of both variables in a clinical model resulted in an increased discrimination of individuals with new CVE of 4.72%, according to the integrated discrimination index. Assessment of SBI and ABI less than 0.9 may refine the cardiovascular risk stratification in patients with hypertension.

Does TGFBR3 Polymorphism Increase the Risk of Silent Cerebral Infarction in Egyptian Children with Sickle Cell Disease?

ObjectivesTo evaluate the relationship between TGFBR3 rs284875 single nucleotide polymorphism (SNP) state and silent cerebral infarction (SCI) in asymptomatic patients with sickle cell disease (SCD).MethodsA cross-sectional study was conducted on 50 children with SCD above 2 y of age followed up at the hematology outpatient clinic of Alexandria University Children's Hospital in Egypt. Twenty-four healthy children were included as a control group. All patients included in the study were subjected to complete history and clinical examination. Real-time polymerase chain reaction was performed on patients and controls for identification of SNP rs284875 of the TGFBR3 gene. A magnetic resonance imaging (MRI) of the brain were performed only on patients for detection of SCI.ResultsFifty SCD patients were enrolled (26 males and 24 females), with a median age of 10.9 y (2.3–17.8 y), and 24 children as healthy control for the studied SNP. Thirty-five (70%) patients had homozygous SCD, while 30% had sickle β-thalassemia. The brain MRI was normal in all the patients except for 2 patients who had features of SCI. The TGFBR3 rs284875 SNP was detected in 15 (30%) patients in the homozygous state (GG) versus only 1 (4.2%) child from the control group (p = 0.003). The prevalence of SCI was low in the study population and there was no statistically significant relationship between the TGFBR3 rs284875 SNP status and the presence of SCI in the brain MRI (p = 0.621).ConclusionsThis study confirmed a low prevalence of SCI in the SCD patient included in the study. The TGFBR3 rs284875 SNP did not significantly increase SCI among those patients.

Quantification of Silent Cerebral Infarction on High-Resolution FLAIR and Cognition in Sickle Cell Anemia.

Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8–30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24–42% in patients, and 4–23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue.

Detecting the vulnerable carotid plaque: the Carotid Artery Multimodality imaging Prognostic study design.

Carotid artery disease is highly prevalent and a main cause of ischemic stroke and vascular dementia. There is a paucity of information on predictors of serious vascular events. Besides percentage diameter stenosis, international guidelines also recommend the evaluation of qualitative characteristics of carotid artery disease as a guide to treatment, but with no agreement on which qualitative features to assess. This inadequate knowledge leads to a poor ability to identify patients at risk, dispersion of medical resources, and unproven use of expensive and resource-consuming techniques, such as magnetic resonance imaging, positron emission tomography, and computed tomography. The Carotid Artery Multimodality imaging Prognostic (CAMP) study will: prospectively determine the best predictors of silent and overt ischemic stroke and vascular dementia in patients with asymptomatic subcritical carotid artery disease by identifying the noninvasive diagnostic features of the 'vulnerable carotid plaque'; assess whether 'smart' use of low-cost diagnostic methods such as ultrasound-based evaluations may yield at least the same level of prospective information as more expensive techniques. We will compare the prognostic/predictive value of all proposed techniques with regard to silent or clinically manifest ischemic stroke and vascular dementia. The study will include ≥300 patients with asymptomatic, unilateral, intermediate degree (40-60% diameter) common or internal carotid artery stenosis detected at carotid ultrasound, with a 2-year follow-up. The study design has been registered on Clinicaltrial.gov on December 17, 2020 (ID number NCT04679727).

Impact of Medication Adherence on the Association Between Oral Anticoagulant Use and Risk of Dementia: A Retrospective Cohort Study using the Japanese Claims Database.

BackgroundAtrial fibrillation (AF) is a major risk factor for the development of stroke and silent cerebral infarct (SCI). Additionally, AF is independently associated with neurological disorders, including cognitive impairment and dementia. Although oral anticoagulants (OACs) are used to reduce the risk of development of stroke and SCI in patients with AF, it is unclear whether OACs reduce the risk of dementia.ObjectiveThis study aimed to investigate the association between OAC use and dementia in relatively young patients with AF. Moreover, the impact of medication adherence on the association between OAC use and the risk of dementia was examined.Patients and MethodsThis retrospective cohort study was conducted using a large claims database—Japan Medical Data Center, Inc. (JMDC)—from which newly diagnosed patients with AF younger than 75 years of age were identified. We analyzed medication adherence using the medication possession ratio (MPR). The dementia risk was compared between the OAC and non-OAC groups using Cox proportional hazards regression analysis and the Kaplan–Meier method after propensity score matching. Similarly, the MPR-classified and non-OAC groups were also compared.ResultsOAC administration was not associated with the risk of dementia in the entire cohort (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.40–1.08; p = 0.098); however, OAC administration in patients with an MPR ≥90% was significantly associated with a lower risk of dementia (HR 0.45, 95% CI 0.25–0.81; p = 0.008). Meanwhile, direct OAC (DOAC) and warfarin (WF) administration was not associated with the risk of dementia regardless of MPR. Kaplan–Meier analysis revealed a significant difference in the incidence of dementia between the MPR ≥ 90% OAC and non-OAC groups (log-rank test: p = 0.006). However, no difference was observed in the incidence of dementia between the MPR ≥ 90% WF and non-OAC groups, or between the MPR ≥ 90% DOAC and non-OAC groups.ConclusionsOAC administration was not associated with the risk of dementia in relatively young patients with AF; however, when limited to patients with an MPR ≥ 90%, OAC administration reduced the risk of dementia. Our results suggest that the association between OAC use and dementia should be evaluated while considering medication adherence.

Risk factors of Silent Cerebral Infarcts in Patients with Acute Coronary Syndrome Based on MRI Findings

Risk factors of Silent Cerebral Infarcts in Patients with Acute Coronary Syndrome Based on MRI Findings

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait.

Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

Assessment of functional shunting in patients with sickle cell disease.

Silent cerebral infarcts (SCI) are common in patients with sickle cell disease (SCD) and are thought to be caused by a mismatch between oxygen delivery and consumption. Functional cerebrovascular shunting is defined as reduced oxygen offloading due to the rapid transit of blood through the capillaries caused by increased flow and has been suggested as a potential mechanism underlying reduced oxygenation and SCI. We investigated the venous arterial spin labeling signal (VS) in the sagittal sinus as a proxy biomarker of cerebral functional shunting, and its association with hemodynamic imaging and hematological laboratory parameters. We included 28 children and 38 adults with SCD, and ten healthy racematched adult controls. VS, cerebral blood flow (CBF), velocity in the brain feeding arteries, oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) were measured before and after acetazolamide administration. VS was higher in patients with SCD compared to controls (P<0.01) and was increased after acetazolamide administration in all groups (P<0.01). VS was primarily predicted by CBF (P<0.01), but CBF-corrected VS was also associated with decreased CMRO2 (P<0.01). Additionally, higher disease severity defined by low hemoglobin and increased hemolysis was associated with higher CBF-corrected VS. Finally, CMRO2 was negatively correlated with fetal hemoglobin, and positively correlated with lactate dehydrogenase, which could be explained by changes in oxygen affinity. These findings provide evidence for cerebral functional shunting and encourage future studies investigating the potential link to aberrant capillary exchange in SCD.

Comparison of frequency of silent cerebral infarction as assessed by serum neuron specific enolase in patients with non-valvular atrial fibrillation: Warfarin versus direct oral anticoagulant

Background Cerebral infarction in patients with atrial fibrillation (AF) may clinically vary from being silent to catastrophic. Silent cerebral infarction (SCI) is the neuronal injury in the absence of clinically appearent stroke or transient ischaemic attack. Serum neuron specific enolase (NSE) is suggested to be a valid surrogate biomarker that allows to detect recent neuronal injury. We aimed to evaluate the incidence of recent SCI by positive NSE levels in patients with non-valvular AF (NVAF) on oral anticoagulants. Methods Blood samples for NSE were collected from 197 consecutive NVAF patients. NSE levels of greater than 12 ng/ml was considered as positive and suggestive of SCI. Results Patients were mainly female with a mean age of 69 years. Ninety-eight of them (49.7%) were taking warfarin. Mean INR level was 2.3 ± 0.9. Mean CHA2DS2-VASc score of the study population was 3.5 ± 1.5. Seventy-two patients (36.5%) were found to have NSE elevation. They were more likely to have history of chronic heart failure and previous stroke/TIA. Increased left atrial diameter and higher CHA2DS2-VASc were other factors associated with SCI. Patients on DOACs and patients taking aspirin on top of oral anticoagulant treatment were less likely to have SCI. Multivariate analysis demonstrated that increased left atrial diameter (OR: 2.5; 95% CI: 1.52–4; p < 0.001) and use of warfarin (OR: 2.8; 95% CI: 1.37–5.61; p = 0.005) were detected as independent predictors of SCI. Conclusions Our study revealed that DOACs were associated with significantly reduced SCIs compared with warfarin, probably due to more effective and consistent therapeutic level of anticoagulation.

Evolution of Extracranial Internal Carotid Artery Disease in Children With Sickle Cell Anemia.

Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis. Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review. Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT (P=0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT (P=0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events. Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

Transcranial Doppler sonography and the effect of haematopoietic stem cell transplantation in sickle cell disease

BackgroundSickle cell disease (SCD) is one of the most prevalent monogenetic diseases worldwide and one of the most serious complications is stroke. Transcranial Doppler (TCD) demonstrated to be highly predictive for an imminent stroke by measuring blood flow velocities in the basal cerebral arteries. Currently, the only curative therapy for SCD is hematopoietic stem cell transplantation (HSCT). The aim of this study is to verify the correlation between blood flow velocities and stroke including the effect of HSCT.MethodsIn our retrospective single-center study a total of 26 sickle cell patients (HbSS, HbSß+-thalassemia, HbSSα-thalassemia minima, HbSSα-thalassemia minor and HbSC) were analyzed between 2010 and 2016. The highest time averaged maximum mean blood flow velocity (TAMMV) measured was documented and evaluated with respect to SCD genotype and effect of HSCT. Acute and symptomatic as well as silent strokes were recorded as separate parameters.ResultsIn our study, ten patients had normal blood flow velocities before HSCT (six HbSS and four HbSß+-thalassemia patients) and 13 patients presented with abnormal TCD (eight HbSS, three HbSSα-thalassemia minima, one HbSSα-thalassemia minor and one HbSC). Thirteen of 26 study participants (ten HbSS and three HbSß+-thalassemia patients) received HSCT. In two patients, TAMMV in basal cerebral arteries remained “normal”, in one they remained conditional and in one TAMMV was reduced to normal. Four of 26 study participants (15.4%), including all patients with HbSS genotype, presented with a stroke, but none had “abnormal” TAMMV with TCD performed after the onset of stroke in each case. At the time we performed the TCD, the patients had already suffered the stroke.ConclusionIn our study, none of the patients with stroke displayed abnormal blood flow velocities in TCD. Yet, HSCT at this stage of the disease still had a positive effect on TAMMV. Further studies are needed whether this effect converts into reduced stroke risk at all or only selected SCD patients undergoing HSCT.